Dihydropyridine calcium channel blockers are useful in the treatment of cardiovascular and cerebrovascular disorders. These agents act by inhibiting calcium uptake into vascular smooth muscle cells and mobilizing calcium from their intracellular stores. The vascular smooth muscle relaxes leading to vasodilation, decreased peripheral vascular resistance and decreased blood pressure. Examples of dihydropyridine calcium channel blockers include: amlodipine (NORVASC®), bepridil, diltiazem (CARDIZEM®), felodipine (PLENDIL®), isradipine (DYNACIRC®), mibefradil, nicardipine hydrochloride (CARDENE®), nifedipine (ADALAT® and PROCARDIA®), nimodipine (NIMOTOP®), nisoldipine (SULAR®), verapamil (CALAN®, ISOPTIN® and VERELAN®) and nilvadipine.
Nicardipine has a number of pharmaceutically acceptable salts, including the hydrochloride salt (e.g., IUPAC chemical name (±)-2-(benzyl-methyl amino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride). The preparation and use of nicardipine hydrochloride are described in U.S. Pat. No. 3,985,758. CARDENE® (nicardopine hydrochloride) is sold commercially in several forms. For example, nicardipine hydrochloride is available as an immediate release oral capsule, an extended release oral capsule, and as a concentrated preparation provided as an ampule (i.e., CARDENE® I.V.) that is greatly diluted into a pharmaceutically acceptable diluent before administration to a patient. CARDENE® I.V. is indicated for the short-term treatment of hypertension when oral therapy is not feasible or not desirable (see, the product insert for CARDENE® I.V.).
“Injectable” formulations of nicardipine have been described. For example, U.S. Reissue Pat. No. RE. 34,618, a reissue of U.S. Pat. No. 4,880,823, describes an injectable composition of nicardipine hydrochloride that is stored in a light resistant brown ampule and avoids the use of sodium chloride, particularly as a tonicity agent, in the formulation. U.S. Pat. No. 5,164,405 describes a buffered pharmaceutical composition containing nicardipine that is designed for parenteral administration. This composition is also stored in an ampule. A drawback of both these ampule formulations is that they must be greatly diluted into a pharmaceutically acceptable diluent before administration to a patient.
While nicardipine exists in oral and injectable forms, a bolus formulation of nicardipine has not been approved by the FDA. Nevertheless, nicardipine is administered off-label as a bolus injection. Administration requires dilution of the concentrated ampul formulation. See for example, Deanna Cheung, et al., Am Heart J., vol. 119, pp. 438-442 (1990); Albert Cheung et al., Anesth Analg, vol. 89, pp. 1116-1123 (1999); (author), Anesth Analg, vol. 85, pp. 1247-1251 (1997); Yunan Zhang et al., Anesth Analg, vol. 100, pp. 378-381 (2005); John L Atlee et al., Anesth Analg, vol. 90, pp. 280-285 (2000); H J Yang et al., J. Int Med Research, (cite); Jean-Louis Vincent et al., J. CardiothoracicVasc Anesth, vol. 11, pp. 160-164 (1997); Chia-Chen Chen, et al., Acta Anaesthesiol Sin, vol. 34, pp. 197-202 (1996); Y L Kwak, et al., J. Int Med Research, vol. 32, pp. 342-350 (2004); P Colson et al., Acta Anaesth Scand, vol. 42, pp. 1114-1119 (1998); Jean-Marc Bernard et al., Anesth Analg, vol. 75, pp. 179-85 (1992); Hiroshi Endoh et al., J. Clin Anesthesia vol. 11, pp. 545-549 (1999); A G M Aya et al., Intensive Care Med, vol. 25, pp. 1277-1281 (1999); S. Elatrous et al., Intensive Care Med, vol. 28, pp. 1282-1286 (2002); Joseph Flynn et al., J. Pediatr, vol. 139, pp. 38-43 (2001); and other references.
Pharmaceutical compositions that are supplied in ampules have several important drawbacks. For example, these ampule formulations must be diluted into a pharmaceutically acceptable diluent prior to use. Therefore, they are not immediately available for use, such as in an emergency setting. Ampule compositions that must be diluted before use introduce the possibility of dosing errors in making the dilution; and safety hazards associated with the use of glass ampules. In addition, according to guidelines for administration of admixed (premixed) products in hospital settings, admixed solutions should be used within 24 hours in order to minimize the risk of microbial contamination. See The United States Pharmacopeia, vol. 1, p. 349 (2007). In addition to the concerns generally associated with off-label use of ampule formulations, CARDENE® I.V. (nicardipine hydrochloride ampule) presents two additional challenges. First, the pH of the diluted solution varies widely because the concentrated ampule solution can be diluted into various diluents, as described in the product insert for CARDENE® I.V. Second, as shown in the product insert for CARDENE® I.V., the diluted solution is only stable for 24 hours at room temperature. Therefore, the diluted solution must be used relatively quickly or it will expire.
To minimize the possibility of hemolysis, precipitation, phelebitis and pain, drugs which are directly injected into the circulatory system need to have little to no precipitate formed during storage, and upon contact and subsequent dilution in blood following administration (see., e.g., Yalkowsky, et al., 1998, J. Pharmaceutical Sciences, 87(7): 787-796). Nicardipine is a weak organic base, having a pKa of 7.2, and dissolves poorly in water-based formulations, especially at physiological pH. To avoid precipitation of nicardipine when administered in a more concentrated form, its poor aqueous solubility must be overcome. Thus, there is a long-felt need for a low volume, stable aqueous pharmaceutical formulation of nicardipine which can provide a therapeutically effective dosage and which does not appreciably degrade upon storage or precipitate when parenterally administered in a more concentrated, lower volume formulation.
The compositions provided herein address these and other needs by providing a relatively low volume, pre-mixed, ready-to-use, injectable formulation of nicardipine that is stable enough for clinical use, and yet provides a suitable nicardipine concentration for immediate use, without dilution, by parenteral injection.